The High-Affinity Chymotrypsin Inhibitor Eglin C Poorly Inhibits Human Chymotrypsin-Like Protease: Gln192 and Lys218 Are Key Determinants.

Autor: Németh BZ; Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary.; Institute of Molecular Life Sciences, Protein Bioinformatics Research Group, Hungarian Research Network, Budapest, Hungary., Kiss B; Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary., Sahin-Tóth M; Department of Surgery, University of California Los Angeles, California, Los Angeles, USA., Magyar C; Institute of Molecular Life Sciences, Protein Bioinformatics Research Group, Hungarian Research Network, Budapest, Hungary., Pál G; Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary.
Jazyk: angličtina
Zdroj: Proteins [Proteins] 2025 Feb; Vol. 93 (2), pp. 543-554. Date of Electronic Publication: 2024 Sep 20.
DOI: 10.1002/prot.26750
Abstrakt: Eglin C, a small protein from the medicinal leech, has been long considered a general high-affinity inhibitor of chymotrypsins and elastases. Here, we demonstrate that eglin C inhibits human chymotrypsin-like protease (CTRL) weaker by several orders of magnitude than other chymotrypsins. In order to identify the underlying structural aspects of this unique deviation, we performed comparative molecular dynamics simulations on experimental and AlphaFold model structures of bovine CTRA and human CTRL. Our results indicate that in CTRL, the primary determinants of the observed weak inhibition are amino-acid positions 192 and 218 (using conventional chymotrypsin numbering), which participate in shaping the S1 substrate-binding pocket and thereby affect the stability of the protease-inhibitor complexes.
(© 2024 The Author(s). PROTEINS: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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